The mythology of the Johto region features Ho-Oh, the Rainbow Pokémon guardian of the skies, and Lugia, the Diving Pokémon guardian of the seas, who previously perched on the Bell and Brass Towers respectively in Ecruteak City. When the Brass Tower burned down in a storm, Lugia flew away, and three Pokémon died in the process. Ho-Oh revived these Pokémon, creating Raikou, Entei, and Suicune. Lugia's home, the Whirl Islands, were also created when the Pokémon dispelled a war over a singular island, splitting it into four islands and making them its home, producing powerful whirlpools to protect itself. Celebi, the Time Travel Pokémon, also calls Johto its home, residing in the Ilex Forest where it brings Pokémon and Trainers forward and back in time.

100 previously unknown Pokémon reside in Johto. In the Generation II games, the player's home town is New Bark Town, where they can choose either Chikorita, Cyndaquil, or Totodile as his/her first Pokémon.

The Pokémon League

The Johto League is the greatest aspiration of all Trainers. Because they are neighboring regions, Johto and Kanto share the same Elite Four, located at Indigo Plateau. One Badge from each Johto Gym is required to enter.